Calcium is a major component of the mineral phase of bone, and in ionic form plays an important role in cellular signal transduction. In particular, a signaling ligand (the “first messenger”) such as a hormone may exert an effect on a cell to which it binds by causing a short-lived increase or decrease in the intracellular concentration of another molecule (the “second messenger”); calcium is known to play the role of first or second messenger in numerous cellular signaling contexts.
Calcium homeostasis in blood and other extracellular fluids is tightly controlled through the actions of calciotropic hormones on bone, kidneys, and intestine. In humans, dietary intake of calcium approximates 500 to 1000 mg/day, and obligatory endogenous losses in stool and urine total about 250 mg/day. On the order of 30% of calcium in the diet must be absorbed to sustain bone growth in children and to prevent postmenopausal bone loss in aging women. To meet the body's need for calcium, the intestines of most vertebrates evolved specialized vitamin D-dependent and -independent mechanisms for ensuring adequate intestinal calcium uptake. Intestinal absorption of Ca2+ occurs by both a saturable, transcellular process and a nonsaturable, paracellular pathway. When dietary calcium is abundant, the passive paracellular pathway is thought to be predominant. In contrast, when dietary calcium is limited, the active, vitamin D-dependent transcellular pathway plays a major role in calcium absorption.
The transcellular intestinal-uptake pathway is a multistep process, consisting of entry of luminal Ca2+ into an intestinal epithelial cell (i.e., an enterocyte), translocation of Ca2+ from its point of entry (the microvillus border of the apical plasma membrane) to the basolateral membrane, followed by active extrusion from the cell. Intracellular Ca2+ diffusion is thought to be facilitated by a calcium binding protein, calbindin D9K, whose biosynthesis is dependent on vitamin D. The extrusion of Ca2+ takes place against an electrochemical gradient and is mainly mediated by Ca-ATPase. The entry of Ca2+ across the apical membrane of the enterocyte is strongly favored electrochemically because the concentration of Ca2+ within the cell (10−7–10−6 M) is considerably lower than that in the intestinal lumen (10−3 M) and the cell is electronegative relative to the intestinal lumen; as a result, the movement of Ca2+ across the apical membrane does not require the expenditure of energy.
The molecular mechanism responsible for entry of Ca2+ into intestinal cells has, however, been difficult to characterize. In particular, researchers have disagreed as to whether a transporter or a channel is responsible for this process (although studies have indicated that Ca2+ entry is voltage-independent and largely insensitive to classic L-type calcium channel blockers).